High Level Of Toxicity Research Articles

Venetoclax Combined with Cladribine + Low Dose AraC (LDAC) Alternating with 5-Azacytidine Produces High Rates of Minimal Residual Disease (MRD) Negative Complete Remissions (CR) in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

Venetoclax Combined with Cladribine + Low Dose AraC (LDAC) Alternating with 5-Azacytidine Produces High Rates of Minimal Residual Disease (MRD) Negative Complete Remissions (CR) in Older Patients with Newly Diagnosed Acute Myeloid Leukemia (AML)

Green synthesis of silver nanoparticles using Solanum mammosum L. (Solanaceae) fruit extract and their larvicidal activity against Aedes aegyptiL. (Diptera: Culicidae).

The family of mosquitoes (Diptera: Culicidae) contains several species of major public health relevance due to their role as vectors of human disease. One of these species, Aedes aegypti, is responsible for the transmission of some of the most important vector-borne viruses affecting humankind, including dengue fever, chikungunya and Zika. Traditionally, control of Ae. aegypti and other arthropod species has relied on the use of a relatively small diversity of chemical insecticides. However, widespread and intensive use of these substances has caused significant adverse environmental effects and has contributed to the appearance of pesticide-resistant populations in an increasing number of locations around the world, thereby dramatically reducing their efficiency. Therefore, it becomes urgent to develop novel alternative tools for vector control. In that context, our study aimed at evaluating the insecticidal activity against Ae. aegypti of aqueous extracts obtained from the fruits of Solanum mammosum L., as well as silver nanoparticles synthesized using aqueous extracts from this plant species (SmAgNPs). To perform the test, third instar Ae. aegypti larvae were exposed to increasing concentrations of plant extract and SmAgNPs for 24 h. Our results suggest that both the aqueous extract and SmAgNPs were toxic to the larvae, with SmAgNPs displaying a much higher level of toxicity than the extract alone, as reflected in their LC50 values (0.06 ppm vs 1631.27 ppm, respectively). These results suggest that both S. mammosum extracts and SmAgNPs exhibit noteworthy larvicidal activity, and should be further explored as potential source of alternative tools in the fight against insect vectors of human disease.

Data enabled prediction analysis assigns folate/biopterin transporter (BT1) family to 36 hypothetical membrane proteins in Leishmania donovani.

Leishmaniasis is a neglected tropical disease caused by the pathogenic protozoan Leishmania donovani and it is transmitted by an infected sand fly. Approximately 0.4 million cases of Visceral Leishmaniasis are reported across the globe every year, of which 67% is from the Indian subcontinent. The currently available drugs have not been effective owing to their high toxicity levels, inadequate specificity, drug resistance, extended treatment periods and/or prohibitive prices. For this reason, hypothetical proteins in this pathogen, which constitute about 67% of its proteome, must be distinctly characterized and studied for their potential role as drug targets for Leishmaniasis. Domain information from PFAM and functional information from GO has been used to assign putative functions to 36 hypothetical membrane proteins in this protozoan. Furthermore, as a case study, we have performed a thorough sequence level characterization of a hypothetical protein E9BPD7 from the BT1 family of membrane proteins that transports folate/biopterin. Phylogenetic analyses of E9BPD7 have revealed interesting evolutionary correlations to BT1 family and MFS superfamily, which have significant roles in a number of diseases and drug resistance pathways.

River toxicity assessment using molecular biosensors: Heavy metal contamination in the Turag-Balu-Buriganga river systems, Dhaka, Bangladesh

Pollution in rapidly urbanising cities and in delta systems is a serious problem that blights the lives and livelihoods of millions of people, damaging and restricting potable water supply and supplies to industry (Whitehead et al, 2015, 2018). Employing new technology based on luminescent molecular biosensors, the toxicity in the rivers around Dhaka in Bangladesh, namely the Turag, Tongi, Balu and Buriganga, has been assessed. Samples taken at 36 sites during medium and low flow conditions and during the Bishwa Ijtema Festival revealed high levels of cell toxicity, as well as high concentrations of metals, particularly aluminium, cadmium, chromium, iron, zinc, lithium, selenium and nickel. Chemical analysis also revealed low dissolved oxygen levels and anoxic conditions in the rivers at certain sites. The bacterial molecular biosensors were demonstrated to be fast, with results in 30 min, robust and a highly sensitive method for the assessment of water toxicity in the field. Furthermore, the biosensor toxicity analysis correlated with the metals data, and a multivariate regression relationship was developed relating toxicity to key metals, such a selenium, zinc and chromium. The resulting model has been validated against split samples and the Bishwa Ijtema Festival data. The combination of modelling and the molecular biosensor technology provides a new approach to detecting and managing pollution in urban river systems.

Human Biomonitoring of Trace Elements in Scalp Hair from Healthy Population of Pakistan.

The present study deals with the assessment of essential trace and toxic elements in biological samples (scalp hair) of healthy smoker and non-smoker residents of Lahore (the second most populous city), Pakistan. Human biomonitoring of various trace elements like zinc (Zn), iron (Fe), copper (Cu), chromium (Cr), cadmium (Cd), nickel (Ni), lead (Pb), and arsenic (As) was evaluated in human hair samples of smokers and non-smokers (males and females) as per IFCC criteria. For the purpose of comparison, scalp hair samples of age- and sex-equivalent healthy persons were also analyzed. The results of this study show that the concentrations (P95 values) of As (0.17, 0.81, and 0.91μg/g), Cd (2.80, 3.81, and 3.16μg/g), Cr (4.1, 4.2, and 5.3μg/g), Cu (20.0, 21.0, and 21.9μg/g), Ni (3.9, 4.6, and 4.3μg/g), Pb (4.0, 4.8, and 5.0μg/g), and Fe (49.0, 49.0, and 59.3μg/g) were significantly higher in scalp hair samples of smokers than in referents, for various age groups (16-32years, 33-50years, and 51-62years), respectively. The concentrations of Zn (165, 163, and 173μg/g various age groups, respectively) in similar age group were found lower in the scalp hair samples of smokers than referents. Exposure of high toxic metal level through smoking and deficiency of Zn could be synergistic with the risk factors associated with the use of tobacco. Correlation studies for the elements in cigarette with the elements in scalp hair of male smokers show a highly positive correlation between Cr-Cd, Cr-Ni, Cu-Fe, and Ni-Zn.

Safety lead-in of the MEK inhibitor trametinib in combination with GSK2141795, an AKT inhibitor, in patients with recurrent endometrial cancer: An NRG Oncology/GOG study

ObjectiveWe sought to determine safety and efficacy of the AKT inhibitor, GSK2141795, combined with the MEK inhibitor, trametinib, in endometrial cancer. MethodsPatients with measurable recurrent endometrial cancer were eligible. One to two prior cytotoxic regimens were allowed; prior use of a MEK or PI3K pathway inhibitor was excluded. Initial trial design consisted of a KRAS mutation stratified randomized phase II with a safety lead-in evaluating the combination. For the safety lead in, the previously recommended phase 2 dose (RP2D; trametinib 1.5 mg, GSK2141795 50 mg) was chosen for Dose Level 1 (DL1). ResultsOf 26 enrolled patients, 14 were treated on DL1 and 12 were treated on DL-1 (trametinib 1.5 mg, GSK2141795 25 mg). Most common histologies were endometrioid (58%) and serous (27%). Four of 25 (16%) patients were KRAS mutant.Dose limiting toxicities (DLTs) were assessed during cycle 1. DL1 had 8 DLTs (hypertension (n = 2), mucositis (2), rash (2), dehydration, stroke/acute kidney injury). DL1 was deemed non-tolerable so DL-1 was explored. DL-1 had no DLTs. Sixty-five percent of patients had ≥ grade 3 toxicity.There were no responses in DL1 (0%, 90%CI 0–15%) and 1 response in DL-1 (8.3%, 90%CI 0.4–33.9%). Proportion PFS at 6 months for DL1 is 14%, and 25% for DL-1. ConclusionThe combination of trametinib and GSK2141795 had high levels of toxicity in endometrial cancer at the previously RP2D but was tolerable at a reduced dose. Due to insufficient preliminary efficacy at a tolerable dose, the Phase II study was not initiated.

Leaching of insecticides used in blueberry production and their toxicity to red worm.

Soil columns were collected from a blueberry field, and insecticide solutions were allowed to leach through these columns. Insecticides from four different chemical classes were applied at two different rates: the concentration at which the insecticides wash off blueberries under rainfall conditions and the labeled field rate at which they are sprayed. The soil columns were divided into thirds; top, middle and bottom. Soil bioassays using Eisenia foetida Savigny, as an indicator species, were set up to determine the toxicity of the insecticides at a top, middle and bottom layer of the soil column. The mass of E.foetida was also measured after the bioassay experiment was completed. The concentrations at which insecticides wash-off of blueberries from rainfall were not lethal to E.foetida. In order to support mortality data, insecticide residues were quantified in the soil layers for each insecticide. Under field rate leaching conditions, carbaryl showed the high levels of toxicity in the top and middle layers of soil suggesting that it has the highest risk to organisms from leaching. This study will help blueberry growers make informed decisions about insecticide use, which can help minimize contamination of the environment.

In Vitro study of Garcinia celebica L. Stem Barks against Hepatitis C virus and Hepatocellular Carcinoma

In this study, we are focused on Garcinia celebica as anti-HCV activity against JFH1 strain genotype 2a. The extraction process employed the use of maceration method. Starting from n-hexane solvent and another residue. The extracts were then analysed with various doses of 20, 10, 5, 2.5, and 1.25 μg/mL for anti-HCV against JFH1 strain genotype 2a and anticancer against Huh7it-1 cell line. The extracts exhibited anti-HCV on 1.25 μg/mL and no sign of toxicity to Huh7it-1 cells. The extracts also expressed anticancer activity on 20, 10, 5, and 2.5 μg/mL with a high level of toxicity to Huh7it-1 cells. The results from this study suggest that Garcinia celebica may be necessary as an add-on therapy candidate for treating HCV infections and HCC.

In Vitro Evaluation of the Inhibitory Effect of Topical Ophthalmic Agents on Acanthamoeba Viability.

PurposeTo compare the antimicrobial effect of topical anesthetics, antivirals, antibiotics, and biocides on the viability of Acanthamoeba cysts and trophozoites in vitro.MethodsAmoebicidal and cysticidal assays were performed against both trophozoites and cysts of Acanthamoeba castellanii (ATCC 50370) and Acanthamoeba polyphaga (ATCC 30461). Test agents included topical ophthalmic preparations of common anesthetics, antivirals, antibiotics, and biocides. Organisms were exposed to serial two-fold dilutions of the test compounds in the wells of a microtiter plate to examine the effect on Acanthamoeba spp. In addition, the toxicity of each of the test compounds was determined against a mammalian cell line.ResultsProxymetacaine, oxybuprocaine, and especially tetracaine were all toxic to the trophozoites and cysts of Acanthamoeba spp., but lidocaine was well tolerated. The presence of the benzalkonium chloride (BAC) preservative in levofloxacin caused a high level of toxicity to trophozoites and cysts. With the diamidines, the presence of BAC in the propamidine drops was responsible for the activity against Acanthamoeba spp. Hexamidine drops without BAC showed good activity against trophozoites, and the biguanides polyhexamethylene biguanide, chlorhexidine, alexidine, and octenidine all showed excellent activity against trophozoites and cysts of both species.ConclusionsThe antiamoebic effects of BAC, povidone iodine, and tetracaine are superior to the current diamidines and slightly inferior to the biguanides used in the treatment for Acanthamoeba keratitis.Translational RelevanceOphthalmologists should be aware that certain topical anesthetics and ophthalmic preparations containing BAC prior to specimen sampling may affect the viability of Acanthamoeba spp. in vivo, resulting in false-negative results in diagnostic tests.

Visible light-induced apoptosis activatable nanoparticles of photosensitizer-DEVD-anticancer drug conjugate for targeted cancer therapy

The therapeutic efficacy of photodynamic therapy (PDT) in cancer treatment is attributed to the conversion of tumor oxygen into reactive singlet oxygen (1O2) using photosensitizers. However, poor tissue penetration and rapid oxygen depletion have limited the effectiveness of PDT. Therefore, we have developed visible light-induced apoptosis activatable nanoparticles of the photosensitizer (Ce6)-caspase 3 cleavable peptide (Asp-Glu-Val-Asp, DEVD)-anticancer drug monomethyl auristatin E (MMAE) conjugate, resulting in Ce6-DEVD-MMAE nanoparticles. The average size of self-assembled Ce6-DEVD-MMAE nanoparticles was 90.8 ± 18.9 nm. Compared with conventional PDT based on high-energy irradiation, the new therapy uses lower-energy irradiation to induce apoptosis of cancer cells, and activation of caspase 3 to successfully cleave the anticancer drug MMAE from the Ce6-DEVD-MMAE nanoparticles, resulting in strong cytotoxic effects in cancer cells. Notably, the one-time activation of MMAE in the Ce6-DEVD-MMAE nanoparticles further amplified the cytotoxic effect resulting in additional cell death in the absence of visible light irradiation. Furthermore, Ce6-DEVD-MMAE nanoparticles passively accumulated in the targeted tumor tissues via enhanced permeation and retention (EPR) effect in mice with squamous cell carcinoma (SCC7). The high levels of toxicity were retained after exposure to lower-energy irradiation. However, Ce6-DEVD-MMAE nanoparticles did not show any toxicity in the absence of exposure to visible light irradiation, in contrast to the toxicity of free MMAE (1–10 nM). Thus, the light-induced therapeutic strategy based on apoptotic activation of Ce6-DEVD-MMAE nanoparticles can be used to treat solid tumors inaccessible to conventional PDT.

A new series of acetohydroxamates shows in vitro and in vivo anticancer activity against melanoma

Cancer treatment is challenging, mainly due to high levels of drug toxicity and the resistance of tumours to chemotherapy. Hydroxamic acid derivatives have recently aroused attention due to their potential to treat malignancies. In the present study, we sought to investigate the anticancer effects of a new series of synthetic acetohydroxamates. The in vitro cytotoxic and antiproliferative effects of 11 synthetic acetohydroxamates were evaluated against the melanoma cell line A375. Apoptosis, cell cycle, and autophagy assays were employed to elucidate the cell death pathways induced by the compounds. The in vivo pharmacokinetic profiles of the most promising compounds were determined in CD-1 mice, while the in vivo antitumour efficacies were evaluated using the A375 melanoma xenograft model in nude mice. MTT assays revealed that all compounds presented concentration-dependent cytotoxicity against the A375 cell line. AKS 61 produced the most favourable antiproliferative activity according to the sulphorhodamine B and clonogenic assays. AKS 61 treatment resulted in decreased mitochondrial membrane potential and increased apoptosis and autophagy in the A375 cell line. However, AKS 61 failed to prevent in vivo tumour growth in a melanoma xenograft, whereas compound AKS 7 was able to inhibit tumour growth when administered orally. These in vivo findings may be explained by a more favourable pharmacokinetic profile presented by AKS 7 when compared to AKS 61. Taken together, these results suggest that acetohydroxamates have potential anticancer effects and will guide future optimisation of these molecules to allow for further non-clinical development.

Studying and Assessing the Toxicity of Calcium Oxide Nanoparticles under One-Time Inhalation Exposure

Under a single 4 hour inhalation exposure to aerosol containing an aqueous suspension of calcium oxide nanoparticles (CaO) in an actual concentration of 6.68 mg/m3, the accumulation of calcium increased in the lungs (by 1.52 times), in the brain (by 1.55 times) and in the liver (by 1.25 times) relative to the control, while exposure to a microdispersed analog in a concentration of 6.37 mg/m3 resulted in an increase in the indicator only in the brain (by 1.27 times). At the same time, the calcium concentration in the brain of animals in the experimental group is higher than in the comparison group (by 1.22 times). After exposure to CaO nano- and microparticles a subarachnoid hemorrhage in the brain tissues was found. The development of pathomorphological changes in the form of lymphoid tissue hyperplasia, eosinophilia, acute arterial plethora, and hemorrhagic lung infarcts, as well as the hydropic and hyaline-drop dystrophy of parenchymal liver tissue was observed only after exposure to CaO nanoparticles. The identified features of the bioaccumulation and pathomorphological changes under inhalation exposure to CaO nanoparticles demonstrate that the studied nanomaterial has a higher level of toxicity in comparison to its microdispersed analog.

Morphological and molecular phylogenetic identification and record verification of Gambierdiscus excentricus (Dinophyceae) from Madeira Island (NE Atlantic Ocean)

The marine benthic dinoflagellate genus Gambierdiscus currently contains ~ 16 species that can be highly morphologically similar to one another, and therefore molecular genetic characterization is necessary to complement the morphological species determination. Gambierdiscus species can produce ciguatoxins, which can accumulate through the food chain and cause ciguatera fish poisoning. Recent studies have suggested that Gambierdiscus excentricus may be one of the main species responsible for ciguatoxin production in the temperate and tropical regions of the eastern Atlantic. The present study definitively identifies the species, G. excentricus, from Madeira Island, Northeast-Atlantic Ocean (32° 38′ N 16° 56′ W) by examining the morphology of a strain using light and scanning electron microscopy and sequencing regions of the ribosomal DNA (D8-D10 LSU, SSU rDNA). Variability in the shape of the apical pore and the microarchitecture of the apical pore plate were documented for the first time, as well as variability in the width of the second antapical plate. The first SSU rDNA sequence for the species is reported. Because G. excentricus is known to produce high levels of CTX-like compounds, its presence and toxicity should be regularly monitored to establish whether it is the primary cause of the ciguatera poisoning events on Madeira Island.

Characterization and antimicrobial mechanism of CF-14, a new antimicrobial peptide from the epidermal mucus of catfish

In this study, we identified a novel antibacterial peptide, RIVELTLPRVSVRL-NH2 (named CF-14), derived from the epidermal mucus of catfish and characterized its antimicrobial activity. Analysis of antimicrobial activity and hemolytic activity of CF-14 revealed broad spectrum, high levels of antimicrobial activity and low toxicity to eukaryotic cells. CF-14 remained stable at pH values ranging from 4.0 to 12.0 and remained bioactive when exposed to high temperature. CD analysis indicated that CF-14 forms a random coil in PBS buffer and an α-helical conformation in the membrane-mimetic 2.5% SDS micelle. Additionally, the antibacterial mechanism of CF-14 against Shewanella putrefaciens was investigated. Membrane permeability experiments confirmed that CF-14 could increase cell wall membrane permeability and cause nucleotide leakage. Moreover, observations performed using scanning electron and confocal microscopy indicated that CF-14 could penetrate into the cell membranes of S. putrefaciens and accumulate in bacterial cells, but did not break down cell membranes. Further, electrophoresis analysis demonstrated that CF-14 possesses DNA-binding affinity. The results provide a substantial basis for future application of CF-14, a novel cell-penetrating peptide (CPP) derived from catfish.

Abstract 1236: Subclinical doses and choice of replication stress inducer in combination with CHK1 inhibitors for optimal tumor control and immune responses in vitro and in vivo

Abstract Background: Lung cancer and melanoma are responsible for almost 25% of cancer deaths in Australia. Despite recent progress with targeted and immuno-therapies, the 5 year survival rate in late stage patients is still<20%. CHK1 inhibitors are being investigated as chemosensitizing agents with agents that increase replication stress, primarily Gemcitiabine. Clinical trials of this combination have shown some good responses but high levels of normal tissue toxicity. Materials and methods: Here we have investigated the molecular basis of sensitivity to CHK1 inhibitors as combinations with subclinical doses of hydroxyurea (HU) in melanoma and non-small cell lung cancer (NSCLC) tumor spheres and cell lines in 2% O2 conditions and xenograft models in immune compromised mice and with humanized immune systems. Results: We report that low dose HU increased the sensitivity of >70% of both melanoma and NSCLC cell lines to CHK1 inhibitor (GDC-0575) triggered apoptosis, with complete loss of viability found with clinically achievable doses of this combination. Similar sensitivity was observed in xenograft models of both melanoma and NSCLC. We also demonstrate that a low dose of Gemcitabine combination with CHK1 inhibitor results in complete loss of proliferative potential in normal tissue, whereas normal tissue retaining proliferative potential after treatment with even high doses of hydroxyurea in combination with CHK1 inhibitor. In vivo, this translates to minimal effect on lymphocyte populations in the blood. The combination also triggers an inflammatory response involving the recruitment of macrophages, associated with increased HMGB1 nuclear staining. Immune responses were also assessed in humanized mouse models. Discussion: These data indicate that the combination of low dose HU and CHK1 inhibitor have strong anti-cancer activity in the setting of melanoma and NSCLC cancer, and triggers an inflammatory response, and is likely to be better tolerated than current combinations with Gemcitabine. Our data suggest a significant proportion of melanoma and lung cancer patients could benefit from treatment with this drug combination, and this appears to include an immune response to the tumor. Citation Format: Zay Yar Oo, Martina Proctor, Alex Stevenson, Deborah Nazareth, Jill Larsen, Nikolas Haass, Brian G. Gabrielli. Subclinical doses and choice of replication stress inducer in combination with CHK1 inhibitors for optimal tumor control and immune responses in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1236.

Оцінка екотоксичності пестицидів з використанням тваринних тест-організмів

The following article is the result of biotesting of ecotoxicological danger of pesticides, which are used in gardening. Ten pesticide preparations were selected for the research, six of them are fungicides: flint-star, chorus, score, stroby, topsin-M and median-extra and four of them are insecticides: bi-58, calypso, mospilan and actara. Toxicity of pesticides was identified through analyzing ten times dilution (1:10) of the recommended solution specified by the manufacturer. Not less than three days old tap water served as control. Daphnia, Ostracoda and Danio were selected as test objects. After 1, 2, 3, 4, 5, 24 and 72 hours of exposure the number of dead animals was visually determined and the percentage of survival of testers was calculated. The toxicity of the pesticide preparations was considered as proven if the percentage of test organisms mortality rate was ≥50%. The scale of pesticide toxicity degree was developed, including the percentage of test organisms mortality during certain exposure time (up to 24 or 48 hours). It can be used to define its acute and toxic effect. According to the biotesting results, flint-star and score are the most toxic among the examined pesticide preparations fungicides for aquatic ecosystems, as they showed ultrahigh and high levels of toxicity for zootests. Carp fishes of the genus Danio showed greater sensitivity to the influence of fungicides and lower to insecticides, while for aquatic crustaceous Daphnia and Ostracoda these features were not detected. The sensitivity of the tested test objects to insecticides decreased in an order: Ostracoda sp.→Daphnia sp.→Danio sp. Comparing the sensitivity of aquatic crustaceous in the process of the pesticides biotesting, it was found out that Ostracoda sp. is more sensitive test object than Daphnia sp. Under the same conditions of biotesting, an absolute immobilization of ostracods is two times higher than the immobilization of Branchiopoda.

Toxicity of crude organic extracts from the zoanthid Palythoa caribaeorum: A biogeography approach

Marine isolates such as palytoxin (PTX) are of concern within the Caribbean region due to their toxicity. PTX for example has been described as a one of the most known potent marine toxins, known to prevent predation from larger species (e.g. vertebrates) as well as the prevention of being overgrown from other coral species. PTX is a polyhydroxylated polyether toxin with a very large and complex chemical structure that possesses both hydrophilic and lipophilic properties. Previous acute toxicity tests using brine shrimp (Artemia salina) and PTX extract had shown it to be moderately toxic. In humans, PTX has been credited to be responsible for extreme symptoms such anaphylactic shock, rapid cardiac failure and eventual death occurring within minutes. Extrapolation for human dose ranges has therefore been suggested to be between 2.3 and 31.5 μg. This study isolates a potentially PTX-enriched extract from Palythoa caribaeorum and examines its organic extract toxicity from a biogeography perspective from a within-colony to a variety of reef sites around Trinidad and Tobago that are popular for marine visitors. This research represents an acute study with a high level of crude organic extract toxicity on A. salina whilst postulating potential factors which may contribute to its extreme toxicity and the risk posed to users of these environments.

The Anti-obesity Effects of Direct Delivery of Resveratrol-encapsulated Liposomes to Inguinal White Adipose Tissue in Male APOE*3Leiden.CETP Transgenic Mice (P21-006-19)

ObjectivesBrowning of white adipose tissue (WAT) is a promising strategy for preventing and treating obesity. Trans-resveratrol (R) has the potential to increase the energy expenditure via inducing WAT browning, but its application in obesity is limited by a low level of aqueous solubility, a high level of hepatic metabolism and toxicity. We have successfully synthesized biocompatible and biodegradable R encapsulated liposomes (Rlipo). The objective of this project is to deliver Rlipo directly to the inguinal WAT (iWAT) in mice with the goal of maximizing anti-obesity efficacy while minimizing side effects and toxicity. MethodsRlipo were prepared using R and soy phosphatidylcholine (soy-PC) dissolved in ethanol. After mixing and drying them under nitrogen, deionized water was added followed by sonication. Unencapsulated R was removed by ultrafiltration. The void liposomes (Vlipo) were prepared using only soy-PC.The particle size and polydispersity index (PI) of Rlipo and Vlipo were measured using a Brookhaven BI-MAS particle size analyzer. R’s encapsulation efficiency and solubility were measured using a liquid chromatography-mass spectrometry.Male APOE*3Leiden.CETP mice having human-like lipoprotein metabolism were fed with a high-fat diet (45% of calorie from fat) for 10 weeks. After treating the high-fat diet for 4 weeks, mice received iWAT injection of Rlipo, Vlipo, free R and saline (control) once a week. R concentration was 17.5 mg/kg body weight/week. Body weight and food intake were measured weekly. Body composition of mice was measured using an EchoMRITM every other week. Core body temperatures of mice were determined using a Type T thermometer. Glucose tolerance test (GTT) was performed at the 4th week of treatment. ResultsRlipo increased the aqueous solubility of R by more than 100 times. The size of Rlipo and Vlipo was 170 ± 6 nm and 140 ± 7 nm, respectively. Their PI values were less than 0.2. The encapsulation efficiency of Rlipo was 99.8%. The post-treatment core body temperatures for control, free R, Vlipo and Rlipo groups were 36.2°C, 36.2°C, 36.6°C, and 37.0°C, respectively. Food intake was similar among 4 groups. Compared to other groups, the Rlipo-treated mice had the lowest body weight, body fat mass, and body fat percentage. The Rlipo group had the lowest area under the curve in the GTT among 4 groups. ConclusionsNanoencapsulation increased R’s solubility and enhanced its anti-obesity efficacy. Funding SourcesNIH/NCCIH (Grant R15AT008733).

The Importance of Otoneurological Evaluation in Brazilian Workers Exposed to Pesticides: A Preliminary Study.

Introduction Agrochemicals, also known as pesticides, are widely used in agriculture and in public health. They are organic and inorganic chemical substances with a high level of toxicity not only for the environment, but also for human health. Objective To verify findings on labyrinthine assessment in endemic disease control agents, and to recommend the inclusion of the vestibular exam in the set of tests for pesticide-exposed populations. Methods Descriptive, prospective, cross-sectional study with a sample comprising 15 endemic disease control agents, males, mean age of 51.6 years old (standard deviation [SD] = 5.9). All of the participants were submitted to anamnesis, otorhinolaryngological screening, and vestibular assessment. Results Regarding the most reported complaints, dizziness (73.4%), headache (60%), and tingling in the extremities (53.4%) were observed. The findings of the vestibular exams were normal in 53.3%, while 46.7% showed peripheral vestibular disorder, of which 26.7% were of deficitary type, and 20% of the irritative type. Conclusions: Alteration in the vestibular system was verified in 50% of the workers, with a greater prevalence in the caloric testing. Several disorders related to pesticides intoxication are scientifically known. Actions promoting knowledge and qualification of this population for the proper handling of chemicals are suggested, in addition to the elaboration and inclusion of protocols of vestibular assessment in hearing health programs for the prevention, diagnosis and treatment of vestibular disorders.

Heavy metal resistance genes and plasmid-mediated quinolone resistance genes in Arthrobacter sp. isolated from Brazilian soils.

Arthrobacter sp. are Gram-positive bacilli commonly obtained from soil and in the hospital environment. These species have been reported to cause several types of infection. Heavy metals are a threat to the ecological system due to their high-levels of toxicity and the fluoroquinolones are antimicrobials widely used for the treatment of different bacterial infections. The aim of this study was to investigate the resistance to fluoroquinolone and heavy metals, the presence of plasmid-mediated resistance (PMQR) genes and heavy metals resistance (HMR) genes and the presence of plasmids in Arthrobacter sp. obtained from Brazilian soils. Bacterial isolation was performed using soil samples from different Brazilian regions. The bacterial identification was performed by 16S rRNA gene sequencing. The resistance profile for fluoroquinolones and heavy metals was determined by MIC. Several PMQR and HMR genes and plasmid families were investigated by PCR. Eight isolates were obtained from soil samples from different cultivations and regions of Brazil. All isolates were resistant to all fluoroquinolones, cadmium, cobalt and zinc and the majority to copper. Among the PMQR genes, the qepA (4) was the most prevalent, followed by qnrS (3), qnrB (3), oqxB (2) and oqxA (1). Among the HMR genes, the copA was detected in all isolates and the czcA in two isolates. The replication origin of the ColE-like plasmid was detected in all isolates; however, no plasmid was detected by extraction. The association of resistance to heavy metals and antimicrobials is a threat to the environmental balance and to human health. There are no studies reporting the association of PMQR and HMR genes in bacteria belonging to the genus Arthrobacter. To the best of our knowledge, this is the first report of qnrB, qepA, oqxA and oqxB in Arthrobacter species.